According to the Chinese Ministry of Health, stroke is the second cause of mortality and the first cause of disability in China. There are about 600,000 to 700,000 stroke patients in China, 130,000 to 150,000 new stroke patients and about 100,000 patients died of stroke each year. Among those who survived from the initial symptom onset, about 3 quarters of the patients are disabled to some extents, with about 40% being seriously disabled. Each year China spends more than 30 billion RMB for stroke health care.
According to the American Heart Association and American Stroke Association, there are now more than 700,000 new strokes that occur each year, resulting more than 200,000 deaths per year in the Unite States alone. Ischemic stroke accounts for 80% of this total. Stroke is the leading cause of adult disability in North America and the first cause for inpatient Medicare reimbursement for long term adult care. The National Institute of Health (NIH) estimates that stroke costs now exceed $45 billion US dollars in health care per year.
Ischemic stroke is characterized by complex spatial and temporal events evolving over hours or even days. Within the centre or core of the ischemic territory, blood flow deficits, low ATP (adenosine triphosphate) levels and energy stores, ionic disruption and metabolic failure are severe, and cell death progresses in minutes. However, the peripheral zones within the flow-compromised territory—the ischemic penumbra—suffer milder insults due to residual perfusion from collateral blood vessels. During the early stages of vessel occlusion, the penumbra might compromise as much as a third to half the lesion volume, and actively metabolizes glucose. In this preinfarct margin of metabolically and ionically challenged, metastable tissues, cells die more slowly as the penumbra collapses and the lesion expands over time. In the penumbra, active cell death mechanisms are recruited, and targeting these mechanisms provides promising therapeutic approaches. Within the core territory, salvage of rapidly dying brain cells might not be feasible without early reperfusion.
The concept of ischemic penumbra is now more than 20 years old and has become increasingly important as the potential for treating acute ischemic stroke. Perhaps the simplest but most clinically and pharmacologically relevant definition is “ischemic tissue potentially destined for infarction but not yet irreversibly injured and the target of acute therapy”. The reliable detection of the ischemic penumbra would provide much important information for both clinicians and researchers.
Positron emission tomography (PET) is the only modality clinically validated to accurately identify infarction and penumbra. However, due to its limited availability and long post-processing time, PET cannot be used clinically to guide acute stroke therapy.
Magnetic resonance diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) are increasingly available at major hospitals worldwide for the acute evaluation of stroke patients. Many groups have evaluated the utility of the mismatch model: DWI can delineate reduced water molecular diffusion as hyperdense regions while PWI can show a larger area of compromised tissue perfusion early after stroke onset; when the PWI lesion volume is at least 1.25 times as large as that of the DWI lesion, there is a mismatch. The mismatch model has shown promising results.
However, it is widely recognized that the mismatch model is at best a crude approximation of the ischemic penumbra because 1) the perfusion techniques and data evaluation are not truly quantitative and vary among centers; 2) magnetic resonance PWI is invasive and time consuming, and has not been approved by health authorities; 3) the thresholds used for defining perfusion abnormalities have not been validated against PET thresholds; and 4) abnormal diffusion regions early after stroke onset can be reversed by timely intervention in both animals and humans. As such, it is believed and demonstrated that the mismatch contains both penumbra as well as oligaemia.
Though appropriate thrombolysis can greatly improve prognosis of patients and save lives, inappropriate thrombolysis could cause death and symptomatic brain hemorrhage. Even with the only 2 reported successful intravenous thrombolysis stroke trials by NINDS (National Institute of Neurological Disorders and Stroke) within 3 to 6 hours after symptom onset, there were 10-fold increased risk of symptomatic brain hemorrhage guided by the mismatch model. It is thus critical 1) to extend the time window so that more ischemic patients can be considered for active intervention through image analysis instead of purely based on time of symptom onset; 2) to build up models that take into account of both the existence of penumbra and the likelihood of reperfusion injury due to thrombolysis such as symptomatic brain hemorrhage.
This invention intends to provide a solution to estimating parameters needed for assessing if the patient is suitable for thrombolysis.